Growth inhibition of human keratinocytes by a new vitamin D3 analogue in vitro.
SM-10193 (26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3; F6-1,23(S),25-(OH)3D3) is one of the active vitamin D3 analogues, which is under exploration as a new therapeutic agent for psoriasis. In this paper, we present that SM-10193 induces the growth inhibition and differentiation of cultured normal human keratinocytes more effectively than 1,25(OH)2D3. The growth of keratinocytes was inhibited in the presence of 10(-11), 10(-10), 10(-9), 10(-8), 10(-7) and 10(-6) M of SM-10193 by 36.8, 42.1, 48.5, 47.6, 66.0 and 85.9% respectively. SM-10193 increased the number of involucrin positive cells (the marker for keratinocyte differentiation) from 4.9 +/- 0.1 to 12.5 +/- 0.8, 20.1 +/- 1.6 and 42.8 +/- 1.0% (P < 0.01) at 10(-8), 10(-7) and 10(-6) M, respectively. To elucidate the mechanism of SM-10193-induced growth inhibition, we analyzed cell cycle related distribution and the alteration of hyperphosphorylated and hypophosphorylated state of retinoblastoma protein (pRB). SM-10193 induces growth arrest in G1/G0 and G2 + M phases and an increase of the hypophosphorylated form of pRB more remarkably than 1,25(OH)2D3 does.
Kobayashi
T
T
Department of Dermatology, Osaka University School of Medicine, Japan.
Hashimoto
K
K
Yoshikawa
K
K
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D011565:Psoriasis / Q000188:drug therapy; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism
D016160:Retinoblastoma Protein; C077906:26,26,26,27,27,27-hexafluoro-1,23,25-trihydroxyvitamin D3; D002762:Cholecalciferol; D002117:Calcitriol